Novel Carbamoyl-phosphonates for the Regulation of Tumor Microenvironment

Breuer Eli, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research
Hoffman Amnon, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research
Reich Reuven, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research




  • The process of cancer metastasis consists of a series of sequential events that requires deregulated proliferation and eventually distal dissemination involving detachment from the extracellular matrices and invasion of the surrounding normal tissue
  • Enzymes are critical for multiple processes during malignant progression and are hallmarks in tumor angiogenesis, local and distal invasion and cellular dissemination by acting as part of an extensive multidirectional network. Among them, matrix metalloproteinases occupy central nodes of this process. Localized proteolysis at the tumor-matrix interface signifies the transition from a benign state to a malignant one. Therefore the events in the microenvironment of the transformed cell play a critical role in the progression to malignancy.
  • The enhanced proliferative capacity of tumor cells, owing to the enzyme autotaxin, creates oxygen and nutrient deficient environment. The hypoxia condition initiates several enzymatic pathways including those of specific carbonic anhydrases, enzymes involved in the regulation of intra and extracellular pH, and therefore essential for the survival and proliferation of the cancer cells.

Our Innovation

A novel family of compounds that target three types of cancer-related extra-cellular zinc dependent enzymes:

  • matrix metalloproteinases (MMP2 and 9) involved in tumor metastasis dissemination, and
  • two tumour-related carbonic anhydrases (CAs 9 and 12) that regulate the pH in the microenvironment and
  • autotaxin (ATX) promoting tumor cell proliferation.
  • Our orally bioavailable novel compounds self-target only into the extracellular space where the zinc-dependent enzymes also operate. Being unable to enter the cells by crossing lipid cell-membranes due to their polar nature, there are no toxic side effects observed in the course of such joint anti-cancer action
  • The unique zinc binding group (ZBG) of the ionic carbamoylphosphonates (CPO) assures solubility in the extracellular fluid where the target enzymes operate.
  • The compounds are useful by once daily oral administration, they show no toxicity, including musculoskeletal side effects manifested by most other similar drug candidates.

Key Features

  • Oral activity in cancer metastasis models.
  • Water soluble
  • Non toxic
  • The ionic drugs concentrate in the extracellular fluid and do not cross cell membranes.
  • Enzyme selective – our compounds inhibit only the metalloenzymes  CAs & MMPs, which operate in the extracellular fluid and are directly involved in the disease.

Development Milestones       

  • Next phase will be Modifying the molecules in order to reach second generation compounds with optimized potency, affinity, and specificity toward ATX, CAs & MMPs.

Researcher Information          pharmacy.huji.ac.il/eng/staff_win.asp?id=35&type=2

Contact for more information:

Keren-Or Amar
VP, Business Development, Healthcare